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Insulin Activates the α Isoform of Class II Phosphoinositide 3-Kinase*

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The novel class II phosphoinositide (PI) 3-kinases are characterized by the presence of a C-terminal C2 domain, but little is known about their regulation. We find insulin causes a rapid 2–3-fold increase in the activity of PI 3-kinase C2α (PI3K-C2α) in CHO-IR cells, 3T3-L1 adipocytes, and fully differentiated L5L6 myotubes. No insulin-induced activation of PI3K-C2α was observed in cell types known to have low responsiveness to insulin including HEK 293 cells, 3T3-L1 preadipocytes, and undifferentiated L5L6 myoblasts. The mechanism of activation of PI3K-C2α by insulin differs from that of class Ia PI 3-kinases in that insulin stimulation did not cause PI3K-C2α to associate with IRS-1 or insulin receptor. PI3K-C2α existed as a doublet, and insulin stimulation caused a redistribution from the lower molecular weight band to the higher molecular weight band, suggesting phosphorylation-induced bandshift. Consistent with this, in vitro phosphatase treatment reduced the intensity of the upper band back to that seen in unstimulated cells. This suggests that insulin-induced phosphorylation could play a role in regulation of the activity of PI3K-C2α. The finding that insulin activates PI3K-C2α in cell types known to possess a wide range of responses to insulin suggests that PI3K-C2α is a novel component of insulin-stimulated signaling cascades.

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This work was supported by grants from the Medical Research Council and the British Diabetic Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.